Chemotherapy failure remains a significant problem in the treatment of neoplastic disease. Despite initial sensitivity to chemotherapy most tumors become unresponsive during prolonged treatment. This is thought to be due to the outgrowth of drug resistant mutant tumor cells, and is referred to as acquired resistance. Conversely, some tumors appear to be insensitive to therapy from the onset and these are intrinsically resistant.
Both acquired or intrinsic resistance are characterised by the development of resistance to different groups of drugs with no apparent structural or functional similarities, such as vinca alkaloids and anthracyclines. Although the cellular mechanism of drug resistance is multi-factorial, the ability of resistant cells to lower the intracellular concentration of drug appears to be the most common mechanism.
Several agents of diverse chemical structures are known to potentiate the uptake and the cellular toxicity of cytotoxic drugs such as vinca alkaloids and anthracyclines. This is of great clinical importance in the treatment of cancer, particularly as tumors which have developed resistance to chemotherapy may again become sensitive when treated with a cytotoxic drug in combination with a potentiating agent.